Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
Adenomas are benign tumours of epithelial origin which are derived from glandular tissue or exhibit clearly defined glandular structures. Some adenomas show recognisable tissue elements, such as fibrous tissue (fibroadenomas), while others, such as bronchial adenomas, produce active compounds giving rise to clinical syndromes. Tumours in certain organs, including the pituitary gland, are often classified by their histological staining affinities, for example eosinophil, basophil and chromophobe adenomas.
Adenomas may become carcinogenic and are then termed adenocarcinomas. Accordingly, adenocarcinomas are defined as malignant epithelial tumours arising from glandular structures, which are constituent parts of most organs of the body. This term is also applied to tumours showing a glandular growth pattern. These tumours may be sub-classified according to the substances that they produce, for example mucus secreting and serous adenocarcinomas, or to the microscopic arrangement of their cells into patterns, for example papillary and follicular adenocarcinomas. These carcinomas may be solid or cystic (cystadenocarcinomas). Each organ may produce tumours showing a variety of histological types, for example the ovary may produce both muconous and cystadenocarcinoma. In general, the overall incidence of carcinoma within an adenoma is approximately 5%. However, this is related to size and although it is rare in adenomas of less than 1 centimeter, it is estimated at 40 to 50% villous lesions which are greater than 4 centimeters. Adenomas with higher degrees of dysplasia have a higher incidence of carcinoma. Once a sporadic adenoma has developed, the chance of a new adenoma occurring is approximately 30% within 26 months.
Colorectal adenomas represent a class of adenomas which are exhibiting an increasing incidence, particularly in more affluent countries. The causes of adenoma, and its shift to adenocarcinoma, are still the subject of intensive research. To date it has been speculated that in addition to genetic predisposition, environmental factors (such as diet) play a role in the development of this condition. Most studies indicate that the relevant environmental factors relate to high dietary fat, low fibre and high refined carbohydrates.
Colonic adenomas are localised proliferations of dysplastic epithelium which are initially flat, but with increased growth from the mucosal forming adenomas. They are classified by their gross appearance as either sessile (flat) or penduculated (having a stalk). While small adenomas (less than 0.5 millimeters) exhibit a smooth tan surface, penduculated adenomas have a head with a cobblestone or lobulated red-brown surface. Sessile adenomas exhibit a more delicate villous surface. Penduculated adenomas are more likely to be tubular or tubulovillous while sessile lesions are more likely to be villous. Sessile adenomas are most common in the cecum and rectum while overall penduculated adenomas are equally split between the sigmoid-rectum and the remainder of the colon.
The etiology of adenoma of the colon, and in particular the dysplasia-adenoma-carcinoma sequence is thought to occur in the setting of increasing loss of heterozygosity in genes involved in DNA replication accuracy, tumour suppression and oncogene activation. A hereditary predisposition to cancer is found in 1% of colorectal carcinoma patients and in 5-10% of patients with Hereditary Non-Adenomatosis Polyposis. It is thought that for each lesion the loss of heterozygosity must occur in multiple genes. Currently there are a number of mechanisms proposed to account for the known environment, dietary and genetic predispositions to colorectal cancer. Although no consensus has yet been reached, loss of heterozygosity appears to be a common feature.
Adenomas are generally asymptomatic, therefore rendering difficult their early diagnosis and treatment. It is technically impossible to predict the presence or absence of carcinoma based on the gross appearance of adenomas, although larger adenomas are thought to exhibit a higher incidence of concurrent malignancy than smaller adenomas. Sessile adenomas exhibit a higher incidence of malignancy than penduculated adenomas of the same size. Some adenomas result in the production of microscopic stool blood loss. However, since stool blood can also be indicative of non-adenomatous conditions and obstructive symptoms are generally not observed in the absence of malignant change, the accurate diagnosis of adenoma is rendered difficult without the application of highly invasive procedures such as biopsy analysis. Accordingly, there is an on-going need to elucidate not only the causes of adenoma and its shift to malignancy but to develop more informative diagnostic protocols, in particular protocols which will enable the rapid, routine and accurate diagnosis of adenoma at an early stage, such as the pre-malignant stage.
To date, research has focused on the identification of gene mutations which lead to the development of adenoma. In work leading up to the present invention, however, the inventors have surprisingly determined that changes in the level of expression of unmutated genes which are also expressed in healthy individuals are indicative of adenoma development. The inventors have further determined that in relation to colorectal adenomas, diagnosis can be made based on screening for the expression of mRNA gene transcripts corresponding to any one or more of the panel of genes disclosed herein. In this regard, the inventors have still further determined that some of the genes identified herein as being expressed in healthy individuals at significantly lower levels than that observed in individuals who have developed an adenoma do not correlate with any known gene sequences. Accordingly, the inventors have identified a panel of genes which, in addition to facilitating the diagnosis of adenoma development, further facilitate the development of prophylactic and therapeutic protocols directed to modulation of their expression and functional activity and thereby the development of therapeutic and/or prophylactic protocols for treating patients at risk of or who have developed adenomas.